MARVEL on protease mutations at position 74

HIVdb Algorithm: Comments & Scores

T74P is a nonpolymorphic PI-selected accessory mutation that occurs primarily in viruses from patients who have received multiple PIs. It is associated with reduced susceptibility to each of the PIs. It is included in the Boehringer-Ingelheim TPV and Tibotec DRV GSS.

T74S is a polymorphic mutation weakly selected by most PIs and associated with low-level resistance to NFV.

Mutation

FPV/r

IDV/r

NFV

SQV/r

LPV/r

ATV/r

TPV/r

DRV/r

T74P

10

10

15

10

5

10

20

5

T74S

0

0

15

0

0

0

0

0

Footnote:Mutation scores on the left are derived from published literature linking mutations and ARVs (the complete details can be found in the HIVdb Release Notes).

Genotype-treatment correlation

Mutation frequency according to subtype and drug-class experience.

The frequency of each mutation at position 74 according to subtype and drug-class experience. Data are shown for the 8 most common subtypes. The number of persons in each subtype/treatment category is shown beneath the subtype. Mutations occurring at a frequency >0.5% are shown. Each mutation is also a hyper-link to a separate web page with information on each isolate, including literature references with PubMed abstracts, the GenBank accession number, and complete sequence and treatment records.

The first row shows the frequency of the mutation in persons who are PI-naive (indicated in green). The second row shows the frequency of the mutation in persons who have received one or more PIs. The following rows show the frequency of the mutation in persons who have received only a single PI. Mutation rates that differ significantly between treated and untreated isolates are indicated in yellow.

Mutation

PI

NumSeq

NumMut

% Mutant

p

T74A

0

61632

430

0.60

T74A

>=1

13912

217

1.50

0.000

T74A

APV

73

0

T74A

IDV

1178

9

0.70

0.924

T74A

LPV

1238

16

1.20

0.022

T74A

NFV

1175

16

1.30

0.012

T74A

SQV

457

11

2.40

0.000

T74A

ATV

220

2

0.90

0.975

T74A

TPV

0

0

T74A

DRV

8

0

Mutation

PI

NumSeq

NumMut

% Mutant

p

T74E

0

61632

7

0.00

T74E

>=1

13912

18

0.10

0.000

T74E

APV

73

0

T74E

IDV

1178

0

T74E

LPV

1238

1

0.00

0.383

T74E

NFV

1175

0

T74E

SQV

457

0

T74E

ATV

220

0

T74E

TPV

0

0

T74E

DRV

8

0

Mutation

PI

NumSeq

NumMut

% Mutant

p

T74I

0

61632

7

0.00

T74I

>=1

13912

4

0.00

0.251

T74I

APV

73

0

T74I

IDV

1178

0

T74I

LPV

1238

0

T74I

NFV

1175

1

0.00

0.361

T74I

SQV

457

0

T74I

ATV

220

0

T74I

TPV

0

0

T74I

DRV

8

0

Mutation

PI

NumSeq

NumMut

% Mutant

p

T74K

0

61632

40

0.00

T74K

>=1

13912

28

0.20

0.000

T74K

APV

73

0

T74K

IDV

1178

1

0.00

0.757

T74K

LPV

1238

1

0.00

0.730

T74K

NFV

1175

5

0.40

0.000

T74K

SQV

457

0

T74K

ATV

220

0

T74K

TPV

0

0

T74K

DRV

8

0

Mutation

PI

NumSeq

NumMut

% Mutant

p

T74P

0

61632

24

0.00

T74P

>=1

13912

254

1.80

0.000

T74P

APV

73

1

1.30

0.006

T74P

IDV

1178

9

0.70

0.000

T74P

LPV

1238

7

0.50

0.000

T74P

NFV

1175

9

0.70

0.000

T74P

SQV

457

10

2.10

0.000

T74P

ATV

220

0

T74P

TPV

0

0

T74P

DRV

8

0

Mutation

PI

NumSeq

NumMut

% Mutant

p

T74R

0

61632

4

0.00

T74R

>=1

13912

7

0.00

0.001

T74R

APV

73

0

T74R

IDV

1178

1

0.00

0.180

T74R

LPV

1238

0

T74R

NFV

1175

1

0.00

0.180

T74R

SQV

457

0

T74R

ATV

220

0

T74R

TPV

0

0

T74R

DRV

8

0

Mutation

PI

NumSeq

NumMut

% Mutant

p

T74S

0

61632

1616

2.60

T74S

>=1

13912

1086

7.80

0.000

T74S

APV

73

0

T74S

IDV

1178

43

3.60

0.037

T74S

LPV

1238

123

9.90

0.000

T74S

NFV

1175

81

6.80

0.000

T74S

SQV

457

38

8.30

0.000

T74S

ATV

220

4

1.80

0.593

T74S

TPV

0

0

T74S

DRV

8

0

Footnote: Data are not shown for TPV or DRV because there are no data available from persons who have developed virological failure after receiving just one of these PIs; About one-half of the untreated isolates belong to non-subtype B isolates; About 20% of the treated isolates belong to non-subtype B isolates; A page containing summaries for all of the mutations at this position can be found here.

Genotype-phenotype correlation

Phenotypes of top 10 common patterns of drug resistance mutations with mutations at position 74.

Mutation pattern data is not available for T74.

A complete summary of additional in vitro susceptibility data for viruses with T74 obtained using other assays including the Antivirogram can be found here.

Phenotypic coefficients using machine learning

Least Square Regression (LSR) was used to learn the relative contribution of each mutation to the fold decrease in susceptibility for an ARV. The figure on the left (click to enlarge the figure) shows the regression coefficients (which correlate with the contribution to resistance) for the 35 nonpolymorphic PI-resistance mutations shown to contribute decreased susceptibility to at least one PI. A complete description of the method that generates this figure can be found at Rhee et al PNAS 2006.

Genotype-clinical outcome correlation

Studies correlating baseline genotype and virological response to an ARV therapy with or without mutations at 74.

L10F/I/V, K20M/R, L24I, M46I/L, Q58E, L63P, G73S/A, V77I, V82A/F/S/T, I84A/V, L90M were associated with failure to reach RNA <50 copies/ml (p<=0.1) in a univariate analysis. A score that also included I54L/M/T/V, A71I/L/V/T was significantly associated with response in that 63% of persons with <5 total mutations vs 11% with >=5 total mutations had RNA <50 copies/ml. G16E and D60E occurred at baseline in 5 and 9 persons, respectively, but were not associated with VR.

13 PI mutations at baseline were associated with a reduced VR: 10F/I/V, 16E, 33F/I/V, 46I/L, 60E, 84V, 85V, and 90M. RNA decrease >1 log occurred in 100% with <2 mutations, 80% with 2 mutations, 43% with 3 mutations, and 0% with 4-5 mutations. In a follow-up study of 53 patients (Marcelin 2006), only four mutations (L10F/I/V, L33F/I, I84V, and L90M were predictive of reduced response, although the original score remained predictive.

V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, and L89V at baseline were associated with a decreased VR to DRV/r. About 60% with 0, 45% with 1-2, and <=20% with >=3 DRMs had RNA <50 copies/ml at wk 24. In phenotypic studies, I50V, I54M, L76V, and I84V reduced susceptibility to the greatest extent. V32I emerged in 30% of failures according to prescribing information.

Ten of the 11 mutations (all except G73S: V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, and L89V) in the previous De Meyer 2008 study and a new mutation T74P were associated with a decreased VR (defined by RNA <50 copies/ml) at W24. In patients who did not received T20, harboring >=3 of these mutations were associated a decreased VR.

26(40%) of patients resulted in VF which was defined as RNA >2.3 at W12. I13V, V32I, L33F/I/V, E35D, M36I/L/V, I47V, F53L,I62V at baseline were associated with increased VF. Adjusted OR for resulting in a VF for one addition of these mutations was 6.2. 11% with <4 , 48% with 4-5 and 100% with >5 these mutations resulted in a VF.

The mutations I15V + M46IL + I54LMV + D60E + L63PT + I84V. Persons with 0 or 1 mutation had a mean 2 log decrease, those with 2 mutations had a median 1.5 log decrease, and those with >=3 mutations had <=0.6 log decreases. Mutations at positions 10, 33, 73, and 90 were negatively associated with response in univariate analyses. In this APV/FPV-naive population, no patient had V32I, I47V, or I50V.

The Genotypic Inhibitory Quotient (GIQ) defined as the median LPV Cmin concentration divided by the number of mutations at the following positions (10, 20, 24, 33, 36, 47, 48, 54, 82, 84). In a multivariate analysis, the GIQ but not the number of mutations was significantly associated with VR.

21 mutations at 16 positions were found to correlate with a decreased VR to TPV/r salvage therapy: L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D, I84V. Each additional mutation was associated with a 0.04 log decreased 2-week and 0.16 log decreased 24 week response. The 24 week response dropped from 1.3 logs when 3 mutations were present to 0.64 logs when 4 mutations were present and was completely lost when 8 mutations were present. Note: The vast majority of isolates used to derive the list belonged to subtype B which is relevant because I13V, K20 mutations, M36I, and H69K are highly common in several non-B subtypes.

79 (55%) patients achieved VR defined by a decrease of >= 1 log or a BLQ in RNA level at week 12. Baseline mutations at 6 positions found to be associated with a lower VR and one with a higher VR were used for GSS: E35D/G/K/N + M36I/L/V - F53L/W/Y + Q58E + Q61D/E/G/H/N/R + H69I/K/N/Q/R/Y + L89I/M/R/T/V. 100% patients with a GSS of -1, 79% with 0, 56% with 1, 33% with 2, 21% with 3 and 0% with 4 achieved VR.